Infant Colic

For Clinical purposes must include all of the following

1. An infant who is less than 5 months of age when the symptoms start and stop

2. Recurrent and prolonged periods of infant crying, fussing or irritability reported by caregivers that occur without obvious cause and cannot be prevented or resolved by caregivers

3. No evidence of infant failure to thrive, fever or illness

‘Fussing’ refers to intermittent distressed vocalisation and has been defined as ‘behaviour that is not quite crying but not awake and content either’. Infants often fluctuate between crying and fussing, so that they are difficult to distinguish in practice

The Committee also decided that for Clinical Research purposes, to diagnose infant colic the child must meet the clinical criteria PLUS both of the following

1. Caregiver reports infant has cried or fussed for 3 or more hours/day during 3 or more days in 7 days in a telephone or face-to-face screening interview with a researcher or clinician

2. Total 24-h crying plus fussing in the selected group of infants is confirmed to be 3 h or more when measured by at least one, prospectively-kept, 24-h behaviour diary

From Nurko S, Benninga M, Faure C, Hyman P, Schechter M, St James-Roberts I. Childhood functional gastrointestinal disorders: neonate/toddler. In: Drossman DA, Chang L, Chey WD, Kellow J, Tack J, et al. eds. Rome IV: The Functional Gastrointestinal Disorders, edn. IV. Raleigh, NC: The Rome Foundation.; 2016, with permission

Organic Causes

Incidence of Organic Cases

Alongside the evidence that most infants who cry a lot in early infancy are healthy and developing normally, a small but important minority have been found to have organic disturbances. For example, two reviews concluded that up to 10 % of infants taken to clinicians because of prolonged crying have an organic disturbance [46, 47]. A study of all the infants who were presented to a Canadian paediatric hospital because of crying or irritability over a period of 1 year found that 12 of 237 (5.1 %) had a serious underlying organic aetiology [48].

Detection and Management of Cases Involving Organic Disturbance

In managing a crying infant, an important first step is to exclude and treat any organic causes that may contribute to the crying. Routine clinical observations and history taking are often sufficient for this purpose: for instance in the Canadian hospital series described above, most cases with organic disturbance were visibly unwell. Since most definitions of infant colic exclude cases involving fever, illness or failure to thrive, cases with an organic aetiology in the first 4 months may be best described as ‘colic-like’. Alternatively, the word colic may be avoided entirely and should not be used with infants over 4 months of age (Table 34.1) [26].

Although there are no universally agreed protocols for identifying organic cases, several expert groups have proposed draft versions. Table 34.2 lists the ‘Red Flags’ for this purpose developed by an international expert group [25] and Fig. 34.1 provides a more detailed workup. An important proviso is that the sensitivity and specificity of these schemes are unknown. Critical evaluation in clinical practice and research should lead to refinement and increase their effectiveness.

Table 34.2
‘Red flags’ for identifying cases where prolonged infant crying may be due to organic disease proposed by an international expert panel

Extreme or high pitched cry

Lack of a diurnal rhythm

Symptoms after 4 months of age

Frequent regurgitation, vomiting, diarrhoea, blood or mucus in stools, feeding difficulties, weight loss

Maternal drug ingestion

Abnormal physical examination

Modified from Gormally S. Clinical clues to organic etiologies in infants with colic. In: Barr RG, St James-Roberts I, Keefe MR (eds.), New Evidence on Unexplained Early Infant Crying: Its Origins, Nature and Management. Skillman, NJ: Johnson & Johnson Pediatric Institute; 2001:133–148, with permission


Fig. 34.1
Algorithm for workup of a crying infant

Research into Specific GI Causes and Dietary Management Options for Infant Crying

Food Allergy

Food allergy , particularly cow’s milk protein allergy, is widely regarded as the most common organic deficit causing prolonged infant crying [49, 50]. Although the incidence is unknown, one estimate is that 2 % of infants overall are food allergic [49]. It is unclear how many such infants cry a lot. Cow’s milk protein allergy probably accounts for less than 5 % of cases of colic [51], and should be considered if the infant has other symptoms such as bloody or mucousy diarrhoea, failure to thrive, poor feeding, significant vomiting, eczema and family history of atopy [52, 53]. In such cases, a limited trial of hypoallergenic formula, or maternal cow’s milk protein elimination diet in exclusively breastfed infants is recommended.

However, the use of hypoallergenic formula or excluding dairy from the mother’s diet cannot be recommended for all infants with colic. The reasons are threefold. First, maternal hypoallergenic diets are difficult to follow and maintain. Second, only a minority of infants with colic respond to cow’s milk protein elimination [49, 54]. Third, the evidence for their use in infant colic is not conclusive. Although at least six randomised trials have suggested extensively hydrolysed formulae—that is, cow’s milk-based formula with the proteins broken down by enzymes—to be effective in managing infant colic [3, 5559], and only two trials have indicated them to be ineffective [60, 61], all trials have methodological limitations. Many were not blinded [55, 59] or inadequately blinded [56, 60], used inappropriate comparators (e.g. dietary modification versus medication [55], a hydrolysed formula versus another hydrolysed formula [57]), were biased by crossover effects [55], or included infants who may not have had true colic [58]. The majority of studies did not clearly describe the method of generating random allocation sequence or the process of randomisation. The effectiveness of partially hydrolysed formulae is more controversial, with one unblinded trial showing effectiveness [62] and the other not [63]. Two studies suggested a completely hydrolysed formula (that is, amino acid-based formula) to be effective, but both had small sample sizes and neither were randomised trials [64, 65]. Studies examining the elimination of cow’s milk protein from the breastfeeding mother’s diet have also yielded contradictory results, with four indicating effectiveness [56, 60, 66, 67] and two not [55, 68]. Two systematic reviews in 2012 concluded that there was evidence to suggest hydrolysed formulae to be beneficial to infants with colic; however, most of the studies had methodological inconsistencies and biases. They concluded that the role of maternal hypoallergenic diets in breastfed infants was less clear [69, 70].

Soy formula has been shown in one randomised trial to be effective [71], with two other poor quality trials supporting this [55, 72]. However, the methodological flaws of the latter two trials mean the results cannot be conclusive. One trial used dicyclomine hydrochloride rather than a true placebo as the comparator [55]. The other was a small trial of 19 infants, and the study was possibly biased by crossover effects [72]. One other trial found soy formula to be just as effective as partially hydrolysed formula, without comparing them to a cow’s milk-based formula [63]. Without a proper placebo for comparison, the results cannot be conclusive. In addition, soy formula is no longer recommended for infants less than 6 months old due to inconclusive evidence that it may cause harm to young infants (through excessive phytoestrogen compounds) [73].

Colonic Gas, Hyperperistalsis and Gut Hormones

Excessive intragastrointestinal air, or colonic gas, has often been proposed as a cause of infant colic. However, little evidence has come forward to support this theory. In 1969, Harley et al. demonstrated radiographically normal gastric outlines during colic episodes [74]. Measures to prevent aerophagia are ineffective in preventing colic [75], and the use of gas-reducing agents such as simethicone are also conclusively ineffective [76, 77]. Moreover, intragastrointestinal gas could be a result of swallowed air from crying—that is, an effect, and not a cause [78].

Early authors proposed that colonic hyperperistalsis , spasms or increased rectal pressure could underlie colic [79]. This is based on the evidence that dicyclomine hydrochloride, an agent that may relax colonic smooth muscle and reduce spasms, is effective in treating colic [8084]. This drug, however, has significant, potentially life-threatening side effects, and therefore is no longer recommended for use in infants. A trial of a herbal tea containing an antispasmodic was also effective [85], but the mixture was associated with possible carcinogenic effects and therefore not recommended [86]. These findings do, however, provide evidence that gut spasms may contribute to colic in some infants. The gut hormones motilin and ghrelin, both stimulators of gastric motility, have been found to be higher in infants with colic compared to controls [87, 88]. Whether these findings have practical applications is not yet clear.

Carbohydrate Malabsorption /Lactose Overload

Many authors have suggested carbohydrate malabsorption, lactose overload or lactase insufficiency as causes for infant colic. The excess carbohydrates, such as lactose, in the gut may cause bloating and discomfort. Excess lactose could be a result of lactase insufficiency or lactose overload from excessive consumption of, for example, lactose-rich human foremilk. However, there is insufficient evidence for this as a cause of colic [51]. Studies examining breath hydrogen levels (a by-product of lactose malabsorption) [8992] and the use of lactase supplementation or lactose elimination have yielded conflicting results [49, 9396]. The evidence for lactose explanations of colic is weak. Other dietary changes, such as altering the concentrations of fibre [97] and carbohydrates in formulae [98], are ineffective in infants with colic.

Gastro-oesophageal Reflux Disease

Gastro-oesophageal reflux disease (GORD) is one of the most debated aetiologies of infant colic. Gastro-oesophageal reflux (GOR ) is defined as the physiological passage of gastric contents into the oesophagus with or without regurgitation and vomiting [99]. GORD, also termed ‘pathological reflux’, is present when reflux of gastric contents causes troublesome symptoms or complications [99], such as oesophagitis and failure to thrive [100]. In infants, there is no symptom or symptom complex that is diagnostic of GORD or predicts response to therapy [99]. GOR, GORD and ‘reflux’ are labels often given interchangeably to infants with colic.

There is widespread belief in the community that GOR/GORD plays a major role in infant colic. At the same time, health professionals extensively prescribe anti-reflux medications to infants with colic. However, the evidence for the role of GOR/GORD is lacking. Studies have failed to demonstrate any association between GOR/GORD and crying in infants [100, 101]. In a study of 151 hospitalised infants with excessive crying, 60 % of whom were less than 3 months old, all infants underwent oesophageal pH monitoring. Crying and fussing duration did not correlate with the number of reflux episodes or the fractional reflux time, both measures of GORD [101]. GORD was associated with frequent vomiting more than five times per day, and feeding difficulties only [101]. The study authors stated that in the absence of frequent overt regurgitation, significant GORD was unlikely, implying that ‘silent reflux’—that is, reflux without vomiting—was an unlikely cause of infant crying. These results are congruent with those from a previous retrospective review of irritable infants who underwent pH monitoring [100]. In contrast, another smaller study of 27 hospitalised infants with colic who all underwent oesophageal pH monitoring found 61.5 % to have GORD [102]. However, most of these infants were more than 3 months old, and the study did not define GORD by fractional reflux time.

Not only is the link between crying and GOR/GORD unclear, but four randomised trials have consistently concluded that anti-reflux medications are ineffective for crying [103106]. This is not surprising, given that systematic reviews have concluded that anti-reflux medications are ineffective in improving all GOR symptoms, including crying [107, 108]. Considering the possibility of their associated adverse effects such as increased risk of infections and later osteoporosis [108110], anti-reflux medications should not be used in managing infants with crying.

Gut Microbiota and the Role of Probiotics

Gut Microbiota

The role of gut microbiota in infant colic has recently been under intense scrutiny. The first study that examined this in 1994 found no significant differences in gut microbiota between infants with and without colic, except for Clostridium difficile (C. difficile) which more frequently colonised infants with colic during the time of peak crying when compared to controls [111]. C. difficile is a bacterium known to cause antibiotic-associated diarrhoea.

Over the last 10 years, an Italian group has documented in four separate cross-sectional studies (n = 56–87) that breastfed infants with colic have different gut microbiota compared to breastfed infants without colic. However, these differences have not been consistent. In their 2004 study, breastfed infants with colic were less frequently colonised by Lactobacillus species than those without colic [112]. Yet, in another study the following year, breastfed infants with and without colic had similar overall colonisation rates but different patterns of Lactobacillus species—Lactobacillus brevis and Lactobacillus lactis lactis colonised only those with colic, while Lactobacillus acidophilus colonised only those without colic [113]. The infants with colic were also more likely to have a family history of atopy [113]. This could be a significant confounder, considering that a study in 2010 suggested that infants with cow’s milk protein allergy have higher gut concentrations of anaerobic and Lactobacillus species, and lower gut concentrations of Bifidobacteria , when compared with non-allergic controls [114]. In 2009, the Italian group suggested breastfed infants with colic had more gas-forming coliforms and E. coli concentrations than those without colic [115]. The group’s 2011 study replicated these findings, and suggested that two out of 27 Lactobacillus strains tested had an antimicrobial effect against six gas-forming coliform species isolated from breastfed infants with colic [116]. This finding is interestingly congruent with the group’s 2004 study showing less Lactobacillus species in infants with colic compared to those without [112], further supporting the notion that infants with colic may have more gas-forming coliform species that contribute to gaseous distension and subsequent distress.

Other studies have also suggested a role of gut microbiota in infant colic. In a 2008 Finnish study of 18 breastfed infants with and without colic, those with colic had higher prevalence of indole-producing coliforms, such as Escherichia and Klebsiella species [117]. In a 2009 study of 36 infants with and without colic, those with colic had lower microbial diversity and greater levels of Klebsiella species, while the control group had Enterobacter and Pantoea species that were not detected in the group with colic [118]. A 2012 Finnish study of 89 healthy infants without colic who were at risk of developing allergies suggested Bifidobacterium and Lactobacillus species to be protective against crying and fussing in the first 3 months of life [119]. A 2013 Iranian study of 70 breastfed infants with and without colic found Lactobacillus acidophilus to be present in 20 % of infants without colic, but absent in those with colic [120].

Two recent studies have implicated Helicobacter pylori (H. pylori) in infant colic. A 2012 Saudi Arabian study of 85 infants with and without colic found a higher proportion of infants with colic had positive H. pylori stool antigen compared to those without colic [121], and similar results were found in a 2013 Egyptian study of 100 infants with and without colic [122]. This finding is interesting considering H. pylori is an organism known to cause chronic gastric inflammation [123, 124], and is a well-known cause of gastritis in adults. However, H. pylori colonisation is often asymptomatic. It may be associated with short-term abdominal pain lasting less than 3 months, but not chronic recurrent abdominal pain in children [125]. There is conflicting evidence for its association with epigastric pain in children [125]. In addition, the prevalence of H. pylori infection in children, although not extensively described, is believed to be very low and, therefore, its role in infants is uncertain. The prevalence of H. pylori in children and adolescents in Europe and North America is less than 10 % [126]. In a study of children in Chile, the prevalence of H. pylori was as low as 1 % at 3 months of age, rapidly increasing after 15 months of age to 20 % at 24 months of age—an age by which colic has well and truly resolved [127].


The most exciting recent development in the search of an effective dietary strategy to manage infant colic is the use of probiotics. Probiotics are ‘live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host’ [128, 129]. Probiotics may affect infant crying by altering gut microbiota, leading to changes in gut-mediated pain perception, gut motility, mucosal layers and gut permeability, reduction in gut inflammation and inhibition of gut bacteria. One particular strain of probiotic, Lactobacillus reuteri, has been shown to be effective in reducing infant crying in four randomised trials of exclusively breastfed infants with colic, at a dose of 1 × 108 cfu per day [130133]. Sample sizes ranged from 50 to 83 in the Italian, Polish and Canadian studies. However, a larger randomised trial of the probiotic in both breastfed and formula-fed infants with colic in Australia (n = 167) concluded it to be ineffective [134]. The most likely reasons for the Australian trial’s controversial results lie in the pragmatic nature of the trial, the use of a more objective and precise measure of primary outcome, the larger sample size involved, and possibly the older age of infants recruited. It is possible that the probiotic was ineffective in infants from Australia because of undetermined differences in infant gut microbiota compared with European or Canadian infants. In addition, one of the Italian studies was not blinded [132], and both Italian studies included exclusively breastfed infants whose mothers were all on dairy-elimination diets [131, 132].

Because of this controversy, a collaboration between the authors of the five aforementioned studies is currently undertaking an individual participant data meta-analysis (IPDMA) to pool data from each individual trial into one dataset for analysis [135]. This creates sufficient power to perform subgroup analyses [136, 137]. Upcoming results from this IPDMA may inform which subgroups of infants with colic can benefit from Lactobacillus reuteri.

Gut Inflammation

The recent interest in the role of gut microbiota in colic has also sparked interest in examining the role of gut inflammation as a cause of colic. A recent study of 36 American term infants reported faecal calprotectin levels to be twice as high in infants with colic than those without [118]. Calprotectin, a calcium-binding protein expressed predominantly by neutrophils, is a marker of gut inflammation. It has been demonstrated to be high in faecal and serum samples of children and adults with inflammatory bowel disease [138, 139] and other paediatric inflammatory conditions such as cow’s milk protein allergy [140], necrotising enterocolitis, coeliac disease and intestinal cystic fibrosis [141].

However, the link between calprotectin and colic is far from conclusive, being directly contradicted by the only other study to examine this association. This Norwegian study of 110 infants less than 10 weeks old (76 with colic, seven with transient lactose intolerance and 27 controls) and 60 children (17 with inflammatory bowel disease, 19 with recurrent abdominal pain and 24 controls) did not find a difference in faecal calprotectin levels between infants with and without colic, despite demonstrating higher levels of faecal calprotectin levels in older children with inflammatory bowel disease compared to those without [142]. This could be partially explained by the huge variability in faecal calprotectin levels found in normal healthy infants, and generally higher levels found in neonates than older children and adults [143147]. Some authors have also suggested that faecal calprotectin levels vary by the type of infant feeding [148] and birth weight [149]. Indeed, there is a lack of consensus for ‘normal cut-point’ levels for faecal calprotectin in infants.

The Gut–Brain Axis

In addition to the proposed interplay of interactions between gut microbiota and gut inflammation in colic, a concept of a microbiota–gut–brain axis is emerging, suggesting a communication between gut microbiota and the brain through neural, humoral and immune pathways [150154]. Direct evidence for an effect of gut microbiota on the brain comes from animal studies, with mice administered certain gut bacteria displaying altered behaviours [151, 155, 156]. Indirect evidence for the gut microbiota–brain association comes from clinical studies. For example, children with autism have been shown to have altered gut microbiota composition [157], and more recently an unpublished Finnish study suggested an association between early gut microbiota and later childhood behaviour [158]. The study followed up 75 infants who received a probiotic versus placebo in the first 6 months of life, and found that 13 years later the group of children who were previously assigned the placebo had higher rates of attention deficit hyperactivity disorder and/or autism diagnoses (17 % of placebo group versus 0 % of probiotic group, p = 0.008), with the diagnosed children having lower concentrations of Bifidobacterium species in their faeces in the first 6 months of life compared to the controls. This concept is particularly interesting given a link reported in two recent studies between migraine and infant colic [159, 160]. However, both studies have significant methodological limitations, such as the cross-sectional and retrospective designs, and the likelihood of recall bias. The role of the gut–brain axis in colic is a fascinating area of research that is currently far from conclusive and will require further clarification.


Despite numerous organic theories proposed to play a role in infant colic, none have been proven to be causal. The interplay between gut microbiota, gut inflammation and the gut–brain axis in infant colic is an exciting and credible concept that is currently supported by limited evidence. Meanwhile, there is still no conclusively effective dietary treatment option for infant colic. The use of hypoallergenic formulae or maternal elimination diets can be trialled for certain crying infants with other associated clinical symptoms, but do not work for all infants with colic. Anti-reflux medications are ineffective. The probiotic Lactobacillus reuteri may be effective in certain subgroups of breastfed infants with colic, but it is not effective where infants are formula-fed.



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Aug 29, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Infant Colic

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